Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A (FANCOLEN-1)

• ClinicalTrials.gov Identifier: NCT03157804
• Recruitment Status: Unknown
• First Posted: May 17, 2017
• Last Update Posted: November 25, 2020
• Sponsor: Hospital Infantil Universitario Niño Jesús, Madrid, Spain
• Collaborators: Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT); Centro de Investigación en Red de Enfermedades Raras (CIBERER); Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz; Hospital Vall d'Hebron; Universitat Autonoma de Barcelona
• Information provided by (Responsible Party): Julian Sevilla, Hospital Infantil Universitario Niño Jesús, Madrid, Spain

Study Description

Brief Summary:

This is an open, Phase I / II clinical trial to evaluate the safety and efficacy of a hematopoietic gene therapy procedure with an orphan drug consisting of a lentiviral vector carrying the FANCA gene for patients with Fanconi Anemia of Subtype A .

CD34 + cells derived from bone marrow and / or mobilized peripheral blood (fresh and / or cryopreserved) from patients with Fanconi subtype A (FA-A), will be transduced ex vivo with a lentiviral vector carrying the gene FANCA (orphan drug) . After transduction the cells will be inoculated in patients in order to restore their hematopoiesis with genetically corrected stem cells.

Condition or disease	Intervention/treatment	Phase
Fanconi Anemia	Procedure: IV administration of Genetically Engineered Hematopoietic Stem/Progenitors Cells (HSPCs); Biological: Genetically Engineered Hematopoietic Stem/Progenitor Cells; Other: Laboratory Biomarker Analysis; Biological: Filgrastim; Drug: Plerixafor; Procedure: Bone Marrow Aspiration	Phase 1; Phase 2

Detailed Description:

The main objective of this open-label Phase I / II clinical trial is to evaluate the safety and therapeutic efficacy of a hematopoietic gene therapy procedure with an orphan drug consisting of a lentiviral vector carrying the FANCA gene for patients with Fanconi's Anemia Subtype A.

The drug to be administered to the patients consists of the cellular product resulting from the transduction of autologous CD34 + cells with the therapeutic lentiviral vector PGK-FANCA.Wpre *.

The dose of cells to infuse in the patients will be that obtained from the transduction process of between 3x10^5 and 4x10^6 CD34 + cells / kg of patient body weight.

The cells will be infused intravenously in a single dose, after complete the transduction process.

Follow-up period: 3 years after infusion of transduced cells. However, patients will be monitored outside the clinical trial over a 10-year period.

Follow-up of the grafted transduced cells will be performed on peripheral blood and bone marrow samples.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Clinical Trial Phase I / II to Evaluate the Safety and Efficacy of the Infusion of Autologous CD34 + Cells Transduced With a Lentiviral Vector Carrying the Gene FANCA in Patients With FA Subtype A (FANCOLEN-1)
• Actual Study Start Date: January 7, 2016
• Actual Primary Completion Date: April 23, 2019
• Estimated Study Completion Date: April 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: Autologous CD34+ cells transducted with PGK-FANCA-Wpre *; CD34 + cells from patients with Fanconi subtype A (FA-A) transduced ex vivo with lentiviral vector carrying the gene FANCA, PGK-FANCA-Wpre*The product to be infused consist of a suspension of transduced CD34^+ cells.

Procedure: IV administration of Genetically Engineered Hematopoietic Stem/Progenitors Cells (HSPCs); Biological: Genetically Engineered Hematopoietic Stem/Progenitor Cells; Undergo infusion of genetically modified hematopoietic progenitor cell therapy; Other Name: Genetically Engineered HSPCs; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Filgrastim; Given subcutaneously (SC); Other Name: Filgrastim XM02, Filgrastim-sndz, G-CSF (Colony Stimulating Factor), Neupogen, r-metHug-CSF, Recombinant Methionyl Human Granulocyte CSF, rG-CSF, Tbo-filgrastim, Zarxio; Drug: Plerixafor; Given SC; Other Name: AMD 3100, JM-3100, Mozobil, SDZ SID 791; Procedure: Bone Marrow Aspiration

Outcome Measures

Primary Outcome Measures :

1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Up to 3 years after infusion of transduced cells ]
   All adverse events will be registered for 3 years from infusion of transduced cells
2. Proportion of patients with at least 0.1 copy of the therapeutic vector per nucleated bone marrow or peripheral blood cells three years after infusion. [ Time Frame: 3 years after infusion of transduced cells ]
   Detection of at least 0.1 copy of the therapeutic vector per nucleated bone marrow cell or peripheral blood cells three years after infusion.

Secondary Outcome Measures :

1. Proportion of patients with clinical hematological response after the infusion of autologous CD34 + cells transduced with the therapeutic lentiviral vector [ Time Frame: 3 years after infusion of transduced cells ]
   Proportion of patients with clinical hematological response (improvement of cell blood counts at least in one hematological lineage).

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients diagnosed with Fanconi Anemia complementation group A (FA-A)
• Minimum age 1 year
• Maximum age 21 years
• Lansky Index> 60%.
• Informed consent in accordance with current legal regulations.
• Number of cells to be transduced: At least 3x10^5 purified CD34+ / kg body weight.
• Negative result in the urine pregnancy test at the baseline visit for women of childbearing age, who should be committed to using an effective contraceptive method during the period of study participation.

Exclusion Criteria:

• Patients with an human leukocyte antigen (HLA) identical family donor.
• Evidence of myelodysplastic syndrome or leukemia, or cytogenetic abnormalities predicting the same in bone marrow aspirates. In this case, the studies carried out two months in advance of the patient's entry into the clinical trial will be considered valid.
• Evidence that the patient to be infused has signs of somatic mosaicism, with hematologic improvement.
• Any illness or concomitant process that in the opinion of the investigator incapacitates the subject for their participation in the study.
• Pre-existing sensory or motor impairment> = grade 2 according to the National Cancer Institute (NCl) criteria.
• Pregnant or lactating women.

Contacts and Locations

Locations

Spain

Hospital Vall d'Hebron

Barcelona, Spain, 08035

Hospital Infantil del Niño Jesus

Madrid, Spain, 28009

Sponsors and Collaborators

Hospital Infantil Universitario Niño Jesús, Madrid, Spain

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)

Centro de Investigación en Red de Enfermedades Raras (CIBERER)

Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz

Hospital Vall d'Hebron

Universitat Autonoma de Barcelona

Investigators

• Study Director: Juan A Bueren; CIEMAT/CIBERER/IIS.FJD

More Information

Publications of Results:

Rio P, Navarro S, Wang W, Sanchez-Dominguez R, Pujol RM, Segovia JC, Bogliolo M, Merino E, Wu N, Salgado R, Lamana ML, Yanez RM, Casado JA, Gimenez Y, Roman-Rodriguez FJ, Alvarez L, Alberquilla O, Raimbault A, Guenechea G, Lozano ML, Cerrato L, Hernando M, Galvez E, Hladun R, Giralt I, Barquinero J, Galy A, Garcia de Andoin N, Lopez R, Catala A, Schwartz JD, Surralles J, Soulier J, Schmidt M, Diaz de Heredia C, Sevilla J, Bueren JA. Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia. Nat Med. 2019 Sep;25(9):1396-1401. doi: 10.1038/s41591-019-0550-z. Epub 2019 Sep 9.

Other Publications:

Adair JE, Sevilla J, Heredia CD, Becker PS, Kiem HP, Bueren J. Lessons Learned from Two Decades of Clinical Trial Experience in Gene Therapy for Fanconi Anemia. Curr Gene Ther. 2017;16(5):338-348. doi: 10.2174/1566523217666170119113029.

Molina-Estevez FJ, Nowrouzi A, Lozano ML, Galy A, Charrier S, von Kalle C, Guenechea G, Bueren JA, Schmidt M. Lentiviral-Mediated Gene Therapy in Fanconi Anemia-A Mice Reveals Long-Term Engraftment and Continuous Turnover of Corrected HSCs. Curr Gene Ther. 2015;15(6):550-62. doi: 10.2174/1566523215666150929110903.

Gonzalez-Murillo A, Lozano ML, Alvarez L, Jacome A, Almarza E, Navarro S, Segovia JC, Hanenberg H, Guenechea G, Bueren JA, Rio P. Development of lentiviral vectors with optimized transcriptional activity for the gene therapy of patients with Fanconi anemia. Hum Gene Ther. 2010 May;21(5):623-30. doi: 10.1089/hum.2009.141.

Jacome A, Navarro S, Rio P, Yanez RM, Gonzalez-Murillo A, Lozano ML, Lamana ML, Sevilla J, Olive T, Diaz-Heredia C, Badell I, Estella J, Madero L, Guenechea G, Casado J, Segovia JC, Bueren JA. Lentiviral-mediated genetic correction of hematopoietic and mesenchymal progenitor cells from Fanconi anemia patients. Mol Ther. 2009 Jun;17(6):1083-92. doi: 10.1038/mt.2009.26. Epub 2009 Mar 10.

Rio P, Navarro S, Guenechea G, Sanchez-Dominguez R, Lamana ML, Yanez R, Casado JA, Mehta PA, Pujol MR, Surralles J, Charrier S, Galy A, Segovia JC, Diaz de Heredia C, Sevilla J, Bueren JA. Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34+ cells from Fanconi anemia patients. Blood. 2017 Sep 28;130(13):1535-1542. doi: 10.1182/blood-2017-03-774174. Epub 2017 Aug 11.

• Responsible Party: Julian Sevilla, M.D.PhD Specialist in Hematology Hemotherapy, Responsible for the Transfusion Service and Unit for the Obtention and Processing of Hematopoietic Progenitors and other cellular therapies at the Hospital Infantil Universitario Niño Jesús de Madrid., Hospital Infantil Universitario Niño Jesús, Madrid, Spain
• ClinicalTrials.gov Identifier: NCT03157804
• Other Study ID Numbers: 2011-006100-12
• First Posted: May 17, 2017
• Last Update Posted: November 25, 2020
• Last Verified: November 2020

Additional relevant MeSH terms:

Fanconi Syndrome; Anemia; Fanconi Anemia; Hematologic Diseases; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Metabolic Diseases; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Plerixafor; Lenograstim; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents